RESEARCH: INFLUENZA
FOLDING PROJECT #18462 PROFILE

Miniproteins are small proteins being designed to fight diseases like the flu. Researchers are using computer simulations to see how changes to miniproteins affect their ability to bind to viruses, hoping to make them better drugs.

Note: This TLDR is a simplication and may not be 100% accurate.

Designed miniproteins are a class of biomolecules with intermediate sizes—larger than small-molecule drugs, but smaller than monoclonal antibodies.

Miniproteins can be computationally designed to tightly bind protein targets for use as potential therapeutics, a promising new avenue for treating infectious disease. Hemagglutinin is a viral fusion protein that allows H1 influenza A (HA) to bind sialic acid on cell surfaces, as well as being involved in the post-endocytosis mechanism of cellular infection.

The Baker lab at University of Washington has developed de novo designed miniproteins that bind hemagglutinin, and improved their binding through affinity maturation (Chevalier et al.

2017).

Many of the mutations seen in affinity-matured sequences are not found in the binding interface, and it remains an open question how these changes lead to higher affinity.

Furthermore, many of the computational predictions of how single-point mutations affect binding deviate significantly from the experimentally determined values. Could all-atom molecular simulation approaches achieve more accurate predictions? In this set of simulations, we aim to use massively parallel expanded ensemble simulations to predict mutational effects on affinities to hemagglutinin.

By pairing these simulations with other simulations aimed at modeling the binding reactions of these miniproteins to hemagglutinin, we aim to have a relatively complete picture of a miniprotein-target binding reaction and how mutations affect it.

These studies are a large-scale investigation on how miniprotein binding reactions work in atomic detail, towards a better understanding of computational design and modulation of miniprotein therapeutics.

---

miniproteins

Engineered proteins of intermediate size.

Miniproteins are designed proteins with sizes between small-molecule drugs and monoclonal antibodies. They can be engineered to bind specific protein targets, making them potential therapeutics for treating diseases.

---

therapeutics

Substances used for treating diseases.

Therapeutics are medical treatments that aim to cure, prevent, or alleviate diseases. This can include drugs, vaccines, and other therapies.

---

hemagglutinin

A viral protein that allows influenza A virus to bind to cells.

Hemagglutinin is a surface protein found on the influenza A virus. It plays a crucial role in allowing the virus to attach to and infect host cells by binding to sialic acid molecules on cell surfaces.

---

affinity maturation

Process of improving the binding affinity of antibodies.

Affinity maturation is a process where antibodies are modified to bind more strongly to their target antigens. This typically involves introducing mutations into the antibody genes, leading to variations in the antibody structure that enhance its binding ability.

---

molecular simulation

Computer-based modeling of molecular interactions.

Molecular simulation is a computational technique used to study the behavior and properties of molecules. It involves simulating the movements and interactions of atoms and molecules over time, allowing researchers to understand how they behave in different environments.